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Differences in the Removal of N-Methyl-N-nitrosourea-methylated Products in DNase I-sensitive and -resistant Regions of Rat Brain DNA¹

Cancer Research Laboratory, Veterans Administration Hospital, Department of Biochemistry, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee 38104

The present study with N-methyl-N-nitrosourea and rat brain DNA was performed in order to study the distribution of alkylated products and the difference in the removal of these products from DNase I-sensitive and -resistant regions of DNA. Nuclei were isolated from N-[³H]methyl-N-nitrosourea-treated rats and incubated in the presence of DNase I (5 µg/ml). Digested DNA was further hydrolyzed in 0.1 N HCl, and the alkylated products were identified by chromatography on a cation-exchange column. Resistant DNA was isolated, hydrolyzed, and again the alkylated products were determined. At 4 hr, the specific activity of all the alkylated products in the sensitive regions of DNA was several times higher than the resistant fraction. The rate of loss for the products was greater in the sensitive than the resistant fractions. O⁶-Methylguanine was removed from the sensitive regions but was more stable in the resistant regions. These results suggest that DNase I-sensitive regions of the DNA are preferentially alkylated by N-methyl-N-nitrosourea and that the alkylated products, including O⁶-methylguanine, are selectively removed from the DNase I-sensitive regions of the DNA.

¹ This investigation was supported by the United States Veterans Administration (4323-01) and by USPHS Research Grant CA-15189 from the National Cancer Institute.

Received 10/10/78. Accepted 4/12/79.